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PITX2 functions as a transcription factor for GPX4 and protects pancreatic cancer cells from ferroptosis.
Wang, Zhiliang; Wu, Di; Zhang, Yue; Chen, Weibo; Yang, Yang; Yang, Yue; Zu, Guangchen; An, Yong; Yu, Xianjun; Qin, Yi; Xu, Xiaowu; Chen, Xuemin.
Affiliation
  • Wang Z; Department of Hepatopancreatobiliary Surgery, Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu Province, China.
  • Wu D; Department of Hepatopancreatobiliary Surgery, Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu Province, China.
  • Zhang Y; Department of Hepatopancreatobiliary Surgery, Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu Province, China.
  • Chen W; Department of Hepatopancreatobiliary Surgery, Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu Province, China.
  • Yang Y; Department of Hepatopancreatobiliary Surgery, Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu Province, China.
  • Yang Y; Department of Hepatopancreatobiliary Surgery, Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu Province, China.
  • Zu G; Department of Hepatopancreatobiliary Surgery, Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu Province, China.
  • An Y; Department of Hepatopancreatobiliary Surgery, Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu Province, China.
  • Yu X; Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong'An Road, Xuhui District, Department of Oncology, Shanghai Medical College, Shanghai Pancreatic Cancer Institute, Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China.
  • Qin Y; Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong'An Road, Xuhui District, Department of Oncology, Shanghai Medical College, Shanghai Pancreatic Cancer Institute, Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China. Electronic address: qinyi@f
  • Xu X; Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, No. 270 Dong'An Road, Xuhui District, Department of Oncology, Shanghai Medical College, Shanghai Pancreatic Cancer Institute, Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China. Electronic address: xuxiaow
  • Chen X; Department of Hepatopancreatobiliary Surgery, Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu Province, China. Electronic address: czcxm007@126.com.
Exp Cell Res ; 439(1): 114074, 2024 Jun 01.
Article in En | MEDLINE | ID: mdl-38710403
ABSTRACT
Ferroptosis inhibits tumor progression in pancreatic cancer cells, while PITX2 is known to function as a pro-oncogenic factor in various tumor types, protecting them from ferroptosis and thereby promoting tumor progression. In this study, we sought to investigate the regulatory role of PITX2 in tumor cell ferroptosis within the context of pancreatic cancer. We conducted PITX2 knockdown experiments using lentiviral infection in two pancreatic cancer cell lines, namely PANC-1 and BxPC-3. We assessed protein expression through immunoblotting and mRNA expression through RT-PCR. To confirm PITX2 as a transcription factor for GPX4, we employed Chromatin Immunoprecipitation (ChIP) and Dual-luciferase assays. Furthermore, we used flow cytometry to measure reactive oxygen species (ROS), lipid peroxidation, and apoptosis and employed confocal microscopy to assess mitochondrial membrane potential. Additionally, electron microscopy was used to observe mitochondrial structural changes and evaluate PITX2's regulation of ferroptosis in pancreatic cancer cells. Our findings demonstrated that PITX2, functioning as a transcription factor for GPX4, promoted GPX4 expression, thereby exerting an inhibitory effect on ferroptosis in pancreatic cancer cells and consequently promoting tumor progression. Moreover, PITX2 enhanced the invasive and migratory capabilities of pancreatic cancer cells by activating the WNT signaling pathway. Knockdown of PITX2 increased ferroptosis and inhibited the proliferation of PANC-1 and BxPC-3 cells. Notably, the inhibitory effect on ferroptosis resulting from PITX2 overexpression in these cells could be countered using RSL3, an inhibitor of GPX4. Overall, our study established PITX2 as a transcriptional regulator of GPX4 that could promote tumor progression in pancreatic cancer by reducing ferroptosis. These findings suggest that PITX2 may serve as a potential therapeutic target for combating ferroptosis in pancreatic cancer.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Pancreatic Neoplasms / Transcription Factors / Gene Expression Regulation, Neoplastic / Reactive Oxygen Species / Homeodomain Proteins / Ferroptosis / Phospholipid Hydroperoxide Glutathione Peroxidase / Homeobox Protein PITX2 Limits: Animals / Humans Language: En Journal: Exp Cell Res Year: 2024 Document type: Article Affiliation country: Country of publication:

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Pancreatic Neoplasms / Transcription Factors / Gene Expression Regulation, Neoplastic / Reactive Oxygen Species / Homeodomain Proteins / Ferroptosis / Phospholipid Hydroperoxide Glutathione Peroxidase / Homeobox Protein PITX2 Limits: Animals / Humans Language: En Journal: Exp Cell Res Year: 2024 Document type: Article Affiliation country: Country of publication: